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Jeffrey K Actor - One of the best experts on this subject based on the ideXlab platform.
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Review: Multiple Roles of Cord Factor in the Pathogenesis of Primary, Secondary, and Cavitary Tuberculosis, Including a Revised Description of the Pathology of Secondary Disease
2015Co-Authors: Robert L Hunter, Chinnaswamy Jagannath, Margaret R. Olsen, Jeffrey K ActorAbstract:Abstract. Tuberculosis, once thought to have been controlled, is now resurgent in many parts of the world. Many gaps exist in understanding the pathogenesis of tuberculosis, especially secondary and cavitary disease. Evidence presented here suggests that Cord Factor (trehalose 6,6’-dimycolate, TDM) is a key driver of these processes. It is the most abundant lipid released by virulent M. tuberculosis (MTB) and can switch between two sets of activities. On organisms, TDM is non-toxic and protects them from killing by macrophages. On lipid surfaces, it becomes antigenic and highly toxic. Caseating granulomas, the hallmark of primary tuberculosis, develop from interaction of TDM with lipid within granulomas. New evidence indicates that secondary tuberculosis begins as a lipid pneumonia that accumulates mycobacterial antigens and host lipids in alveoli before developing conditions for activation of the toxicity and antigenicity of TDM. This rapidly produces caseation necrosis that leads to cavities. Finally, virulent MTB release large amounts of TDM during growth as a pellicle within cavities. We propose that such growth results in activation of the toxicity and antigenicity of TDM at the air interface and that presence of the activated TDM perpetuates the cavity
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Lactoferrin: A Modulator for Immunity against Tuberculosis Related Granulomatous Pathology
Hindawi Limited, 2015Co-Authors: Jeffrey K ActorAbstract:There is great need for a therapeutic that would limit tuberculosis related pathology and thus curtail spread of disease between individuals by establishing a “firebreak” to slow transmission. A promising avenue to increase current therapeutic efficacy may be through incorporation of adjunct components that slow or stop development of aggressive destructive pulmonary pathology. Lactoferrin, an iron-binding glycoprotein found in mucosal secretions and granules of neutrophils, is just such a potential adjunct therapeutic agent. The focus of this review is to explore the utility of lactoferrin to serve as a therapeutic tool to investigate “disruption” of the mycobacterial granuloma. Proposed concepts for mechanisms underlying lactoferrin efficacy to control immunopathology are supported by data generated based on in vivo models using nonpathogenic trehalose 6,6′-dimycolate (TDM, Cord Factor)
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Review Article Lactoferrin: A Modulator for Immunity against Tuberculosis Related Granulomatous Pathology
2015Co-Authors: Jeffrey K ActorAbstract:Copyright © 2015 Jeffrey K. Actor. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. There is great need for a therapeutic that would limit tuberculosis related pathology and thus curtail spread of disease between individuals by establishing a “firebreak ” to slow transmission. A promising avenue to increase current therapeutic efficacy may be through incorporation of adjunct components that slow or stop development of aggressive destructive pulmonary pathology. Lactoferrin, an iron-binding glycoprotein found in mucosal secretions and granules of neutrophils, is just such a potential adjunct therapeutic agent. The focus of this review is to explore the utility of lactoferrin to serve as a therapeutic tool to investigate “disruption ” of the mycobacterial granuloma. Proposed concepts for mechanisms underlying lactoferrin efficacy to control immunopathology are supported by data generated based on in vivomodels using nonpathogenic trehalose 6,6-dimycolate (TDM, Cord Factor). 1
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pathogenesis of post primary tuberculosis immunity and hypersensitivity in the development of cavities
Annals of Clinical and Laboratory Science, 2014Co-Authors: Robert L Hunter, Jeffrey K Actor, Shenan Hwang, Vadim Karev, Chinnaswamy JagannathAbstract:M. Tuberculosis (MTB) is an obligate human parasite even though humans are more resistant than any of the animals used for study. It is a human parasite because only humans develop post primary tuberculosis (TB) in their lungs that mediates transmission of infection to new hosts. The extreme paucity of human lung tissue with post primary TB has forced scientists to study animal models and human tissues that do not have the disease. Consequently, the unique features of post primary TB remain largely unknown and misconceptions are widely accepted. This manuscript presents a revised pathogenesis of post primary TB based on studies of lung tissues of thousands of patients by multiple authors and related literature. Primary TB stimulates systemic immunity that kills organisms and heals granulomas resulting in both protection from disseminated TB and resistance to new infection. Post primary TB, in contrast, requires systemic immunity that it subverts to produce local susceptibility in the apex of the lung. It begins in the part of lung with the lowest ventilation, perfusion and movement and then proceeds to paralyze alveolar macrophages, block the exits and suppress inflammation to further isolate the area with post obstructive pneumonia. This provides a safe place for a small number of MTB to drive prolonged accumulation of host lipids and mycobacterial antigens in an otherwise immune person. After many months, the affected lung suddenly undergoes caseation necrosis with vanishingly few MTB. The necrotic tissue fragments to produce a cavity or hardens to develop fibrocaseous disease. Evidence suggests that this is triggered by a hypersensitivity reaction against Cord Factor and then progresses as the Koch phenomenon against many antigens. MTB grow in perfusion only in dead tissue or on a cavity wall. We anticipate that a more accurate understanding of the pathogenesis of post primary TB will facilitate focusing modern technologies to produce rapid advances in understanding and combating TB.
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trehalose 6 6 dimycolate a coat to regulate tuberculosis immunopathogenesis
Tuberculosis, 2013Co-Authors: Kerry J Welsh, Robert L Hunter, Jeffrey K ActorAbstract:Tuberculosis (TB) remains a significant public health burden worldwide. Treatment of this disease requires a minimum of six months and there is no vaccine available for the most common form of the disease. Increasing evidence suggests that the mycobacterial glycolipid trehalose 6,6' dimycolate (TDM; Cord Factor) plays a key role in the pathogenesis of TB disease. TDM protects the TB bacilli from macrophage-mediated killing, inhibits effective antigen presentation, and reduces the formation of protective T-cell responses. TDM promotes initiation of granuloma formation and likely plays a role in caseation. Furthermore, TDM may contribute to the development of post primary disease. Receptors for TDM were recently described and are expected to contribute to our knowledge of the molecular pathogenesis of TB disease. In this manner, understanding TDM may prove promising towards development of targeted TB therapeutics to limit clinical pathologies.
Ikuya Yano - One of the best experts on this subject based on the ideXlab platform.
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intact molecular characterization of Cord Factor trehalose 6 6 dimycolate from nine species of mycobacteria by maldi tof mass spectrometry
Microbiology, 2005Co-Authors: Yukiko Fujita, Takashi Naka, Michael R Mcneil, Ikuya YanoAbstract:Cord Factor (trehalose 6,6′-dimycolate, TDM) is an unique glycolipid with a trehalose and two molecules of mycolic acids in the mycobacterial cell envelope. Since TDM consists of two molecules of very long branched-chain 3-hydroxy fatty acids, the molecular mass ranges widely and in a complex manner. To characterize the molecular structure of TDM precisely and simply, an attempt was made to determine the mycolic acid subclasses of TDM and the molecular species composition of intact TDM by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for the first time. The results showed that less than 1 μg mycolic acid methyl ester of TDM from nine representative species of mycobacteria and TDM from the same species was sufficient to obtain well-resolved mass spectra composed of pseudomolecular ions [M+Na]+. Although the mass ion distribution was extremely diverse, the molecular species of each TDM was identified clearly by constructing a molecular ion matrix consisting of the combination of two molecules of mycolic acids. The results showed a marked difference in the molecular structure of TDM among mycobacterial species and subspecies. TDM from Mycobacterium tuberculosis (H37Rv and Aoyama B) showed a distinctive mass pattern and consisted of over 60 molecular ions with α-, methoxy- and ketomycolate. TDM from Mycobacterium bovis BCG Tokyo 172 similarly showed over 35 molecular ions, but that from M. bovis BCG Connaught showed simpler molecular ion clusters consisting of less than 35 molecular species due to a complete lack of methoxymycolate. Mass ions due to TDM from M. bovis BCG Connaught and Mycobacterium kansasii showed a biphasic distribution, but the two major peaks of TDM from M. kansasii were shifted up two or three carbon units higher compared with M. bovis BCG Connaught. Within the rapid grower group, in TDM consisting of α-, keto- and wax ester mycolate from Mycobacterium phlei and Mycobacterium flavescens, the mass ion distribution due to polar mycolates was shifted lower than that from the Mycobacterium avium–intracellulare group. Since the physico-chemical properties and antigenic structure of mycolic acid of TDM affect the host immune responses profoundly, the molecular characterization of TDM by MALDI-TOF mass analysis may give very useful information on the relationship of glycolipid structure to its biological activity.
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A murine model of granulomatous colitis with mesenteric lymphadenitis induced by mycobacterial Cord Factor.
Virchows Archiv : an international journal of pathology, 2002Co-Authors: Mitsue Sogawa, Takayuki Matsumoto, Hirokazu Yamagami, Tamaki Yamada, Yuriko Ozeki, Ikuya Yano, Yuji Nakajima, Tetsuo Arakawa, Kenji KanedaAbstract:Granulomatous colitis is a major entity of human intestinal diseases. We previously reported that intravenous injection of mycobacterial Cord Factor (CF), a potent macrophage activator, induced pulmonary granulomas in mice with enhanced production of Th1 cytokines and chemokines. In this study we made a murine model of granulomatous colitis by intramural injection of CF. A single dose of 300 µg CF was injected into the wall of the rat and mouse colon in the form of liposomes. After 1 week granulomas developed at the injection site, extending from the subserosa to the lamina propria, and persisted for longer than 6 weeks. They were composed mainly of ED1-positive macrophages, which often underwent apoptosis, and CD4+ and CD8+ lymphocytes, which preferentially infiltrated around the macrophage accumulation. Myofibroblast proliferation was not prominent, and no appreciable fibrosis resulted after the decline of granulomas. Although the intestinal epithelium was involved in inflammation, tissue injuries such as mucosal erosion or ulceration were not induced. When granulomas were formed near the Peyer's patches, they invaded deeply into the lymphoid tissue, producing many small islands. The mesenteric lymph nodes also had many granulomatous islands in the cortex and medulla, but the liver and spleen displayed no granulomatous changes, suggesting that liposomal CF spreads via the lymphatic vessels from the injection site. The CF-induced colonic granulomas associated with mesenteric lymphadenitis will be useful for investigating human granulomatous colitis.
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immunological properties of trehalose dimycolate Cord Factor and other mycolic acid containing glycolipids a review
Microbiology and Immunology, 2001Co-Authors: Roland Ryll, Yoshio Kumazawa, Ikuya YanoAbstract:Mycolic acids are characteristic fatty acids of Mycobacteriaand are responsible for the wax-like consistence of these microorganisms. Decades of research revealed that mycolic acid-containing g1ycolipids, in particular trehalose-6,6'-dimycolate (TDM, Cord Factor) as their best-studied representative, exert a num ber of immunomodifying effects. They are able to stimulate innate, early adaptive and both humoral and cellular adaptive immunity. Most functions can be associated with their ability to induce a wide range of chemokines (MCP-t, MIP-ta, IL-8) and cytokines (e.g., IL-12, IFN-y, TNF-a, IL-4, IL-6, IL-tO). This review tries to link well-known properties of mycolic acid-containing glycolipids, e.g., stimulation of cellular and humoral immunity, granuloma formation and anti-tumor activity, with recent findings in molecular immunology and to give an outlook on potential practical applications.
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trehalose 6 6 dimycolate Cord Factor of mycobacterium tuberculosis induces foreign body and hypersensitivity type granulomas in mice
Infection and Immunity, 2001Co-Authors: Hirokazu Yamagami, Takayuki Matsumoto, Ikuya Yano, Tetsuo Arakawa, Kenji Kaneda, Nagatoshi Fujiwara, Kazuo KobayashiAbstract:Granulomatous inflammation is characterized morphologically by a compact organized collection of macrophages and their derivatives. It is classified as either a hypersensitivity type or a foreign-body type. Lipid components of the Mycobacterium tuberculosis cell wall participate in the pathogenesis of infection. Strains of M. tuberculosis have Cord Factor (trehalose 6,6'-dimycolate [TDM]) on their surface. To clarify host responses to TDM, including immunogenicity and pathogenicity, we have analyzed the footpad reaction, histopathology, and cytokine profiles of experimental granulomatous lesions in immunized and unimmunized mice challenged with TDM. In the present study, we have demonstrated for the first time that TDM can induce both foreign-body-type (nonimmune) and hypersensitivity-type (immune) granulomas by acting as a nonspecific irritant and T-cell-dependent antigen. Immunized mice challenged with TDM developed more severe lesions than unimmunized mice. At the active lesion, we found monocyte chemotactic, proinflammatory, and immunoregulatory cytokines. The level was enhanced in immunized mice challenged with TDM. This result implies that both nonimmune and immune mechanisms participate in granulomatous inflammation induced by mycobacterial infection. Taken together with a previous report, this study shows that TDM is a pleiotropic molecule against the host and plays an important role in the pathogenesis of tuberculosis.
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trehalose 6 6 dimycolate Cord Factor of mycobacterium tuberculosis induces corneal angiogenesis in rats
Infection and Immunity, 2000Co-Authors: Norio Saita, Ikuya Yano, Nagatoshi Fujiwara, Kazuhiko Soejima, Kazuo KobayashiAbstract:Neovascularization or angiogenesis is required for the progression of chronic inflammation. The mechanism of inflammatory neovascularization in tuberculosis remains unknown. Trehalose 6,6*-dimycolate (TDM) purified from Mycobacterium tuberculosis was injected into rat corneas. TDM challenge provoked a local granulomatous response in association with neovascularization. Neovascularization was seen within a few days after the challenge, with the extent of neovascularization being dose dependent, although granulomatous lesions developed 14 days after the challenge. Cytokines, including tumor necrosis Factor alpha (TNF-a), interleukin-8 (IL-8), IL-1b, and vascular endothelial growth Factor (VEGF), were found in lesions at the early stage (within a few days after the challenge) and were detectable until day 21. Neovascularization was inhibited substantially by neutralizing antibodies to VEGF and IL-8 but not IL-1b. Treatment with anti-TNF-a antibodies resulted in partial inhibition. TDM possesses pleiotropic activities, and the cytokine network plays an important role in the process of neovascularization. The pathogenicity of Mycobacterium tuberculosis is related to its ability to escape killing by macrophages and induce delayedtype hypersensitivity (10). This has been attributed to several components of the M. tuberculosis cell wall. Cord Factor (trehalose 6,69-dimycolate; TDM), which is a surface glycolipid, causes M. tuberculosis to grow in serpentine Cords in vitro. Virulent strains of M. tuberculosis have Cord Factor on their surfaces, whereas avirulent strains do not, and injection of purified Cord Factor into mice induces lesions characterized by chronic granulomatous inflammation (2, 20).
Robert L Hunter - One of the best experts on this subject based on the ideXlab platform.
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Review: Multiple Roles of Cord Factor in the Pathogenesis of Primary, Secondary, and Cavitary Tuberculosis, Including a Revised Description of the Pathology of Secondary Disease
2015Co-Authors: Robert L Hunter, Chinnaswamy Jagannath, Margaret R. Olsen, Jeffrey K ActorAbstract:Abstract. Tuberculosis, once thought to have been controlled, is now resurgent in many parts of the world. Many gaps exist in understanding the pathogenesis of tuberculosis, especially secondary and cavitary disease. Evidence presented here suggests that Cord Factor (trehalose 6,6’-dimycolate, TDM) is a key driver of these processes. It is the most abundant lipid released by virulent M. tuberculosis (MTB) and can switch between two sets of activities. On organisms, TDM is non-toxic and protects them from killing by macrophages. On lipid surfaces, it becomes antigenic and highly toxic. Caseating granulomas, the hallmark of primary tuberculosis, develop from interaction of TDM with lipid within granulomas. New evidence indicates that secondary tuberculosis begins as a lipid pneumonia that accumulates mycobacterial antigens and host lipids in alveoli before developing conditions for activation of the toxicity and antigenicity of TDM. This rapidly produces caseation necrosis that leads to cavities. Finally, virulent MTB release large amounts of TDM during growth as a pellicle within cavities. We propose that such growth results in activation of the toxicity and antigenicity of TDM at the air interface and that presence of the activated TDM perpetuates the cavity
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pathogenesis of post primary tuberculosis immunity and hypersensitivity in the development of cavities
Annals of Clinical and Laboratory Science, 2014Co-Authors: Robert L Hunter, Jeffrey K Actor, Shenan Hwang, Vadim Karev, Chinnaswamy JagannathAbstract:M. Tuberculosis (MTB) is an obligate human parasite even though humans are more resistant than any of the animals used for study. It is a human parasite because only humans develop post primary tuberculosis (TB) in their lungs that mediates transmission of infection to new hosts. The extreme paucity of human lung tissue with post primary TB has forced scientists to study animal models and human tissues that do not have the disease. Consequently, the unique features of post primary TB remain largely unknown and misconceptions are widely accepted. This manuscript presents a revised pathogenesis of post primary TB based on studies of lung tissues of thousands of patients by multiple authors and related literature. Primary TB stimulates systemic immunity that kills organisms and heals granulomas resulting in both protection from disseminated TB and resistance to new infection. Post primary TB, in contrast, requires systemic immunity that it subverts to produce local susceptibility in the apex of the lung. It begins in the part of lung with the lowest ventilation, perfusion and movement and then proceeds to paralyze alveolar macrophages, block the exits and suppress inflammation to further isolate the area with post obstructive pneumonia. This provides a safe place for a small number of MTB to drive prolonged accumulation of host lipids and mycobacterial antigens in an otherwise immune person. After many months, the affected lung suddenly undergoes caseation necrosis with vanishingly few MTB. The necrotic tissue fragments to produce a cavity or hardens to develop fibrocaseous disease. Evidence suggests that this is triggered by a hypersensitivity reaction against Cord Factor and then progresses as the Koch phenomenon against many antigens. MTB grow in perfusion only in dead tissue or on a cavity wall. We anticipate that a more accurate understanding of the pathogenesis of post primary TB will facilitate focusing modern technologies to produce rapid advances in understanding and combating TB.
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trehalose 6 6 dimycolate a coat to regulate tuberculosis immunopathogenesis
Tuberculosis, 2013Co-Authors: Kerry J Welsh, Robert L Hunter, Jeffrey K ActorAbstract:Tuberculosis (TB) remains a significant public health burden worldwide. Treatment of this disease requires a minimum of six months and there is no vaccine available for the most common form of the disease. Increasing evidence suggests that the mycobacterial glycolipid trehalose 6,6' dimycolate (TDM; Cord Factor) plays a key role in the pathogenesis of TB disease. TDM protects the TB bacilli from macrophage-mediated killing, inhibits effective antigen presentation, and reduces the formation of protective T-cell responses. TDM promotes initiation of granuloma formation and likely plays a role in caseation. Furthermore, TDM may contribute to the development of post primary disease. Receptors for TDM were recently described and are expected to contribute to our knowledge of the molecular pathogenesis of TB disease. In this manner, understanding TDM may prove promising towards development of targeted TB therapeutics to limit clinical pathologies.
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il 6 mediates 11βhsd type 2 to effect progression of the mycobacterial Cord Factor trehalose 6 6 dimycolate induced granulomatous response
Neuroimmunomodulation, 2011Co-Authors: April N Abbott, Robert L Hunter, Kerry J Welsh, Shenan Hwang, Paulina Ploszaj, Tina Choudhury, Sydney Boyd, Michael R Blackburn, Jeffrey K ActorAbstract:Granulomatous structures are highly dynamic during active mycobacterial infection, with accompanying responsive inflammation contributing to modulation of pathology throughout the course of disease. The heightened inflammatory response coinciding with initiation and maintenance of newly developing granulomatous structures must be limited to avoid excessive damage to bystander tissue. Modulating the cellular bioavailability of glucocorticoids by local regulation of 11βHSD enzymes within responding tissue and parenchyma would allow controlled inflammatory response during infection. Mycobacterial glycolipid trehalose 6,6′-dimycolate was used to induce strong pulmonary granulomatous inflammation immunopathology. Pulmonary corticosterone was significantly increased at days 3 and 5 after administration. An inverse relationship of 11βHSD1 and 11βHSD2 message correlated with pathology development. Immunohistochemical analysis also demonstrated that 11βHSD2 is expressed in proximity to granulomatous lesions. A role for pro-inflammatory IL-6 cytokine in regulation of converting enzymes to control the granulomatous response was confirmed using gene-disrupted IL-6–/– mice. A model is proposed linking IL-6 to endocrine-derived Factors which allows modification of active corticosterone into inert 11-dehydrocorticosterone at the site of granuloma formation to limit excessive parenchymal damage.
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lactoferrin modulation of mycobacterial Cord Factor trehalose 6 6 dimycolate induced granulomatous response
Translational Research, 2010Co-Authors: Kerry J Welsh, Robert L Hunter, Shenan Hwang, Marian L Kruzel, Jeffrey K ActorAbstract:The immune system responds to tuberculosis (TB) infection by forming granulomas. However, subsequent immune-mediated destruction of lung tissue is a cause of significant morbidity and contributes to disease transmission. Lactoferrin, an iron-binding glycoprotein, has demonstrated immunomodulatory properties that decrease tissue destruction and promote T H 1 immune responses, both of which are essential for controlling TB infection. The Cord Factor trehalose 6,6'-dimycolate (TDM) model of granuloma formation mimics many aspects of TB infection with a similar histopathology accompanied by proinflammatory cytokine production. C57BL/6 mice were injected intravenously with TDM. A subset of mice was given 1 mg of bovine lactoferrin 24 h post-TDM challenge. Lung tissue was analyzed for histological response and for the production of proinflammatory mediators. C57BL/6 mice demonstrated a granuloma formation that correlated with an increased production of interleukin (IL)-1β, IL-6, tumor necrosis Factor-α (TNF-α,) IL-12p40, interferon-gamma (IFN-γ), and IL-10 protein. Mice treated with lactoferrin postchallenge had significantly fewer and smaller granulomas compared with those given TDM alone. Proinflammatory and T H 1 cytokines essential to the control of mycobacterial infections, such as TNF-α and IFN-γ, were not significantly different in mice treated with lactoferrin. Furthermore, the anti-inflammatory cytokines IL-10 and transforming growth Factor-β were increased. A potential mechanism for decreased tissue damage observed in the lactoferrin-treated mice is proposed. Because of its influence to modulate immune responses, lactoferrin may be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection.
Per Kragh Andersen - One of the best experts on this subject based on the ideXlab platform.
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combination of the cationic surfactant dimethyl dioctadecyl ammonium bromide and synthetic mycobacterial Cord Factor as an efficient adjuvant for tuberculosis subunit vaccines
Infection and Immunity, 2004Co-Authors: Lars Holtenandersen, T M Doherty, Karen Smith Korsholm, Per Kragh AndersenAbstract:Recombinant, immunodominant antigens derived from Mycobacterium tuberculosis can be used to effectively vaccinate against subsequent infection. However, the efficacy of these recombinant proteins is dependent on the adjuvant used for their delivery. This problem affects many potential vaccines, not just those for tuberculosis, so the discovery of adjuvants that can promote the development of cell-mediated immunity is of great interest. We have previously shown that the combination of the cationic surfactant dimethyl dioctadecyl ammonium bromide and the immunomodulator modified lipid A synergistically potentiates Th1 T-cell responses. Here we report a screening program for other adjuvants with reported Th1-promoting activity and identify a second novel adjuvant formulation that drives the development of Th1 responses with an extremely high efficacy. The combination of dimethyl dioctadecyl ammonium bromide and the synthetic Cord Factor trehalose dibehenate promotes strong protective immune responses, without overt toxicity, against M. tuberculosis infection in a vaccination model and thus appears to be a very promising candidate for the development of human vaccines.
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combination of the cationic surfactant dimethyl dioctadecyl ammonium bromide and synthetic mycobacterial Cord Factor as an efficient adjuvant for tuberculosis subunit vaccines
Infection and Immunity, 2004Co-Authors: Lars Holtenandersen, T M Doherty, Karen Smith Korsholm, Per Kragh AndersenAbstract:The obligatory intracellular pathogen Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is still among the infectious agents with the most devastating impact globally, despite intense research into the disease. One-third of the world's population is thought to be infected with the bacterium and is at risk of developing the disease, which claims more than two million lives each year (59). The situation is further worsened by the advent of the HIV epidemic and the emergence of multidrug-resistant strains of M. tuberculosis. The only commercially available vaccine, Mycobacterium bovis BCG, is the most widely used vaccine in the world today, with BCG immunizations being used in 172 countries (16). This tremendous vaccine “success” contrasts sharply with the picture drawn from several clinical trials conducted to test the efficacy of BCG. These studies show an unacceptably large variation in the protective effect of the vaccine, ranging from 0 to 80%, and a meta-analysis of the trials concluded that BCG is ineffective in protecting adults from developing disease (17). Potential explanations for this lack of effectiveness include the increasing attenuation of the BCG strain (9), the waning of vaccine efficacy over time (24, 57), and differences in the genetic backgrounds of the tested populations and their levels of exposure to environmental mycobacteria (12, 25). Whatever the reason, a new and more effective TB vaccine remains an urgent international research priority. The ability of the host to control infection with M. tuberculosis resides in the ability to mount an effective cellular immune response (28, 42). Thus, for a vaccine to be protective, the induction of a type 1 (Th1) response is essential. In this regard, the key cytokine in mice (18, 26) and also in humans (19, 34) seems to be gamma interferon (IFN-γ), which activates bactericidal effector mechanisms in the mycobacterial host cell, the macrophage. These include the production of reactive oxygen and nitrogen intermediates, such as hydrogen peroxide and nitric oxide (14, 20). Additionally, phagolysosomal fusion gives rise to intense enzymatic activity and acidification of the vacuole. By these mechanisms, the activated macrophage combats the highly resistant intracellular pathogen, and without IFN-γ, effective macrophage function is greatly restricted. IFN-γ thus serves as the primary marker for effective antimycobacterial immunity. The subunit vaccine approach builds on the concept of boosting the immune response to selected antigens delivered in the form of a well-defined recombinant antigen. Recent research into antigens for use in TB subunit vaccines has been focused on antigens from culture filtrates, and more specifically, on secreted proteins from the culture filtrate (3). This has led to the discovery of immunodominant antigens such as the 6-kDa early secretory antigenic target (ESAT-6) and antigen 85B (Ag85B). When administered as a vaccine, either of these antigens can induce significant immunity against subsequent TB infection, and a fusion molecule containing both is even more effective (4, 11, 47). Compared to live vaccines based on whole mycobacteria, these simple subunit constructs have great advantages when it comes to safety and quality control. However, whereas mycobacterial whole-cell vaccines are often very immunogenic, due to the presence of immunostimulatory molecules such as lipoarabinomannan in the mycobacterial cell wall, subunit vaccines rely on effective adjuvants to elicit the appropriate immunity, since the simplified (synthetic, recombinant, and/or highly purified) antigenic components of the vaccine mostly lack immunogenicity by themselves. A large amount of research has been devoted to the development of adjuvants for human use. Unfortunately, this has proven to be an extremely difficult task, since the properties of effective immunomodulating components are rarely congruent with the strict international regulations concerning vaccine toxicity. Therefore, only very few of the adjuvant vehicles in testing for subunit delivery today are expected to be used in future human vaccines (48). In light of this, it is disappointing that the only adjuvants currently approved for use in humans (alum and MF59) generally promote Th2 immune responses (40, 55). Dimethyl dioctadecyl ammonium bromide (DDA) is a cationic, micelle-forming surfactant with a weak Th1-stimulating effect, and it has been reported to promote protective immunity in mice when tested as an adjuvant for a TB subunit vaccine (40). In an attempt to reach higher levels of protection, several immunomodulators have been tested in combination with DDA. The addition of cytokines such as IFN-γ, interleukin-1 (IL-2), and IL-12 did not alter the long-term effect of the vaccine (40, 54). However, a significant improvement was achieved when the inflammation-promoting molecule monophosphoryl lipid A (MPL) was added to a DDA-based TB subunit vaccine (11). Inspired by this finding, we designed the present study to search for other immunomodulators to include in a future TB subunit adjuvant formulation. The work presented here suggests that DDA mixed with trehalose 6,6′-dibehenate (TDB) makes an effective TB subunit adjuvant with the ability to raise a high level of protective memory immunity comparable to that found in BCG-vaccinated mice.
Nagatoshi Fujiwara - One of the best experts on this subject based on the ideXlab platform.
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trehalose 6 6 dimycolate Cord Factor of mycobacterium tuberculosis induces foreign body and hypersensitivity type granulomas in mice
Infection and Immunity, 2001Co-Authors: Hirokazu Yamagami, Takayuki Matsumoto, Ikuya Yano, Tetsuo Arakawa, Kenji Kaneda, Nagatoshi Fujiwara, Kazuo KobayashiAbstract:Granulomatous inflammation is characterized morphologically by a compact organized collection of macrophages and their derivatives. It is classified as either a hypersensitivity type or a foreign-body type. Lipid components of the Mycobacterium tuberculosis cell wall participate in the pathogenesis of infection. Strains of M. tuberculosis have Cord Factor (trehalose 6,6'-dimycolate [TDM]) on their surface. To clarify host responses to TDM, including immunogenicity and pathogenicity, we have analyzed the footpad reaction, histopathology, and cytokine profiles of experimental granulomatous lesions in immunized and unimmunized mice challenged with TDM. In the present study, we have demonstrated for the first time that TDM can induce both foreign-body-type (nonimmune) and hypersensitivity-type (immune) granulomas by acting as a nonspecific irritant and T-cell-dependent antigen. Immunized mice challenged with TDM developed more severe lesions than unimmunized mice. At the active lesion, we found monocyte chemotactic, proinflammatory, and immunoregulatory cytokines. The level was enhanced in immunized mice challenged with TDM. This result implies that both nonimmune and immune mechanisms participate in granulomatous inflammation induced by mycobacterial infection. Taken together with a previous report, this study shows that TDM is a pleiotropic molecule against the host and plays an important role in the pathogenesis of tuberculosis.
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trehalose 6 6 dimycolate Cord Factor of mycobacterium tuberculosis induces corneal angiogenesis in rats
Infection and Immunity, 2000Co-Authors: Norio Saita, Ikuya Yano, Nagatoshi Fujiwara, Kazuhiko Soejima, Kazuo KobayashiAbstract:Neovascularization or angiogenesis is required for the progression of chronic inflammation. The mechanism of inflammatory neovascularization in tuberculosis remains unknown. Trehalose 6,6*-dimycolate (TDM) purified from Mycobacterium tuberculosis was injected into rat corneas. TDM challenge provoked a local granulomatous response in association with neovascularization. Neovascularization was seen within a few days after the challenge, with the extent of neovascularization being dose dependent, although granulomatous lesions developed 14 days after the challenge. Cytokines, including tumor necrosis Factor alpha (TNF-a), interleukin-8 (IL-8), IL-1b, and vascular endothelial growth Factor (VEGF), were found in lesions at the early stage (within a few days after the challenge) and were detectable until day 21. Neovascularization was inhibited substantially by neutralizing antibodies to VEGF and IL-8 but not IL-1b. Treatment with anti-TNF-a antibodies resulted in partial inhibition. TDM possesses pleiotropic activities, and the cytokine network plays an important role in the process of neovascularization. The pathogenicity of Mycobacterium tuberculosis is related to its ability to escape killing by macrophages and induce delayedtype hypersensitivity (10). This has been attributed to several components of the M. tuberculosis cell wall. Cord Factor (trehalose 6,69-dimycolate; TDM), which is a surface glycolipid, causes M. tuberculosis to grow in serpentine Cords in vitro. Virulent strains of M. tuberculosis have Cord Factor on their surfaces, whereas avirulent strains do not, and injection of purified Cord Factor into mice induces lesions characterized by chronic granulomatous inflammation (2, 20).
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serodiagnosis of hansen s disease leprosy by enzyme linked immunosorbent assay using Cord Factor trehalose 6 6 dimycolate as an antigen
Japanese journal of leprosy : official organ of the Japanese Leprosy Association, 1999Co-Authors: Liya Wang, Ikuya Yano, Nagatoshi Fujiwara, Kazuo Kobayashi, Shinzo Izumi, Norio Saita, N TatsumiAbstract:IgG and/or IgM antibodies against mycobacterial Cord Factor (trehalose 6,6'-dimycolate, TDM) in sera of 65 patients of Hansen's disease (21 cases with smear-positive and 44 cases with smear-negative) and 60 healthy individuals were tested by enzyme-linked immunosorbent assay (ELISA) with TDM purified from Mycobacterium tuberculosis H37Rv as an antigen. Of 65 patients with Hansen's disease, 58 cases (89.2%) had positive results (21 samples from 21 patients, 100% with acid-fast bacilli positive in the lesion, and 37 samples from 44 patients, 84.0% with acid-fast bacilli negative Hansen's disease diagnosed clinically). The sensitivity and specificity of anti-Cord Factor ELISA were higher than those of anti-phenolic glycolipid-I (PGL-I) agglutination test. Among the total, 34 patients were classified clinically into three types of the disease, lepromatous leprosy (LL), borderline lepromatous (BL) and borderline tuberculoid (BT). The antibody titer showed LL > BL > BT, indicating that the elevation of anti-Cord Factor antibody titers appeared to be parallel with the degree of humoral immune response against M. leprae. By using semisynthetic Cord Factor consisting of a single subclass of mycolic acid from M. tuberculosis, it was revealed that sera from patients with Hansen's disease were highly reactive against alpha-mycoloyl Cord Factor (alpha-TDM) and less reactive against methoxy mycoloyl TDM (methoxy TDM), differed from sera of tuberculosis patients, which were highly reactive against both methoxy and alpha-mycoloyl Cord Factor (alpha-TDM). Most of sera from patients with Hansen's disease were more reactive against TMM than TDM, differed from sera of tuberculosis patients which were highly reactive against TDM. ELISA using TDM as an antigen is simple, reproducible and useful for the rapid serodiagnosis of Hansen's disease, especially for smear-negative cases.
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anti Cord Factor trehalose 6 6 dimycolate igg antibody in tuberculosis patients recognizes mycolic acid subclasses
Microbiology and Immunology, 1999Co-Authors: Jiongwei Pan, Nagatoshi Fujiwara, Shiro Oka, Ryoji Maekura, Takeshi Ogura, Ikuya YanoAbstract:The detection of anti-Cord Factor (trehalose 6,6′-dimycolate) IgG antibody in active (smear-and/or culture-positive) and inactive (smear- and culture-negative) tuberculosis patients is a useful serodiagnostic tool that can be used for early clinical diagnosis of the disease. We estimated the titers of antiCord Factor IgG antibody in the sera of tuberculosis patients, and compared them with those of Mycobacterium avium-infected patients. Most of the serum samples obtained from the tuberculosis patients were highly reactive against M. tuberculosis (MTB) Cord Factor isolated from M. tuberculosis H37Rv, a human-type mycobacterial strain, whereas they were less reactive against M. avium (MAC) Cord Factor. Similarly, most of the serum samples of the MAC-infected patients were highly reactive against MAC Cord Factor and less reactive against MTB Cord Factor. These results suggest that anti-Cord Factor IgG antibody recognizes the mycolic acid subclasses as an epitope which comprises Cord Factor, since MTB and MAC Cord Factor differ in mycolic acid subclasses and molecular species composition. To clarify the exact antigenic epitope in Cord Factor and to find out a more sensitive and specific diagnostic test antigen, we examined the reactivity of patients' sera to glycolipids containing trehalose (Cord Factor and sulfolipid) obtained from various mycobacterial species. Furthermore, the reactivity of human antisera to various mycolic acid subclasses (α-, methoxy and keto mycolic acids) of MTB Cord Factor was compared. We found that anti-Cord Factor IgG antibody in the sera of human tuberculosis patients most strikingly recognized methoxy mycolic acid in the Cord Factor of M. tuberculosis, whereas it recognized α- and keto mycolic acids weakly. Pre-absorption studies of antibody with MTB Cord Factor or methoxy mycolic acid methyl ester showed that anti-Cord Factor antibody was absorbed partially, but consistently. This is the first report describing that the specific subclass of mycolic acid from mycobacteria is antigenic in the humoral immune system of human tuberculosis infection.
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production and partial characterization of antibody to Cord Factor trehalose 6 6 dimycolate in mice
Microbiology and Immunology, 1999Co-Authors: Nagatoshi Fujiwara, Shiro Oka, Michio Ide, Kazutoshi Kashima, Takeshi Honda, Ikuya YanoAbstract:Antibody production against the trehalose 6,6'-dimycolate (TDM, Cord Factor) of Rhodococcus ruber, a non-pathogenic species of the Actinomycetales group, was investigated in mice by repeated intraperitoneal injection of TDM in water-in-oil-in-water micelles without carrier protein. The antigenic TDM was isolated and purified chromatographically from the chloroform-methanol extractable lipids of R. ruber. The hydrophobic moiety of this TDM was composed of two molecules of monoenoic or dienoic alpha-mycolic acids with a carbon chain length ranging from C44 to C48 centering at C46. To detect the antibody, an enzyme-linked immunosorbent assay (ELISA) system was employed using plastic plates coated with TDM. The antibody reacted against the TDM of R. ruber. The antibody was reactive in similar fashion against glycosyl monomycolates differing in the carbohydrate moiety, such as that of glucose mycolate (GM) and mannose mycolate (MM), obtained from R. ruber. Moreover, the antibody reacted against mycolic acid methyl ester itself when it was used as the antigen in ELISA, and trehalose did not absorb the antibody to TDM or inhibit the reaction. These results indicate that the epitope of TDM recognized by the antibody is mycolic acid, an extremely hydrophobic part of the molecule. Next, we prepared monoclonal anti-TDM antibody (moAb) in mice myeloma cells to examine its biological activities and the role of humoral immunity in mycobacterial infection. MoAb reacted against the TDM, glycosyl mycolate, and mycolic acid methyl ester in ELISA in the same manner as our polyclonal antibody did. The administration of moAb suppressed granuloma formation in the lungs, spleen, and liver induced by TDM and inhibited the production of interleukin-1 (IL-1) and chemotactic Factor, which is reported to precede granuloma formation.